The Skeletal Clinical Studies program has established four clinical protocols (97-DK-0057, 98-D-0145, 98-D-0146, 99-D-003) for the study and treatment of fibrous dysplasia of bone (FD) and the McCune-Albright Syndrome (MAS). McCune-Albright Syndrome (MAS) is a sporadic disease defined clinically by the triad of cafe-au-lait skin pigmentation with the ?coast of Maine? contour, polyostotic fibrous dysplasia of bone, and hyperfunctioning endocrinopathies, including growth hormone (GH) excess. The molecular etiology of the disease is post-zygotic activating mutations of the GNAS1 gene product, Gs alpha. These mutations lead to overproduction of cAMP, and cause the focal formation of abnormal bone and marrow. Due to the scientific interest in determining the effect of these mutations on bone formation, and the impact of abnormal endocrine function on both normal and fibrous dysplastic bone, a screening and natural history protocol (98-D-0145) and several treatment protocols are currently underway. During the course of our patient evaluations, we have noted that several of our patients have had untreated growth hormone excess, which exacerbated their craniofacial fibrous dysplasia. We have found GH excess is common in patients with MAS (28%) and results in a distinct clinical phenotype characterized by increased morbidity, TRH responsiveness, and prolactin co-secretion, a consistent but inadequate response to treatment with cabergoline, and an intermediate response to long-acting octreotide. We are currently studying the efficacy of a growth hormone receptor antagonist to determine if it will return IGF-1 levels to normal, and if it will, in the long run, prevent the acromegalic overgrowth of craniofacial fibrous dysplastic bone. During the course of evaluating patients for enrollment into the treatment protocols, it became apparent that at least two patients that had been diagnosed elsewhere as having fibrous dysplasia of bone, in fact, did not. In one case, there was an unusual generalized skeletal syndrome characterized by fibro-osseous lesions of the jawbones with a prominent psammomatoid body component, bone fragility, and bowing/sclerosis of tubular bones. This case fits with the emerging profile of a distinct syndrome, with similarities to previously reported cases, some with an autosomal dominant inheritance and others sporadic. We have suggested that the syndrome be named gnathodiaphyseal dysplasia. A detailed pathological study revealed previously unreported features of cemento-ossifying fibroma, including the participation of myofibroblasts and the occurrence of psammomatoid bodies and aberrant mineralization, within the walls of blood vessels. Transplantation of stromal cells grown from the lesion into immunocompromised mice resulted in a close mimicry of the native lesion, including the sporadic formation of psammomatoid bodies, suggesting an intrinsic abnormality of bone-forming cells. The jaw lesions in this patient showed fibro-osseous features with the histopathological characteristics of cemento-ossifying fibroma, psammomatoid variant. This particular case emphasizes that the boundaries between genuine GNAS1-mutation positive fibrous dysplasia and other fibro-osseous lesions occurring in the jawbones should be kept sharply defined, contrary to a prevailing tendency in the literature. In another case, the physical examination of the patient revealed a high-arched palate, and a cafe-au-lait spot on the right ankle with a smooth contour (?coast of California?). The past medical history was significant for hypothyroidism, a subcutaneous lipoma, and an episode of transient but significant thrombocytopenia. Examination of her two children revealed pectus excavatum in both and a non-resolving subcutaneous hemangioma in one child. Radiographs of the patient demonstrated multiloculated lytic lesions within the humerus and the femur with a honeycomb appearance throughout. Histological materials from the previous surgeries were reviewed and new biopsies were taken from both proximal and distal humoral lesions. No evidence of FD was seen, although the lesions were osteomalacic, as are fibrous dysplastic lesions. The examined tissue was characterized by abundant, disorganized tangles of blood vessels. A diagnosis of skeletal angiomatosis was established, which is a rare condition and may or may not be associated with visceral, cutaneous, and soft tissue lesion. The association of angiomatosis with thrombocytopenia (Kasabach-Merritt syndrome), a hyperpigmented skin lesion, varicosities, and a hemangioma in her child raises the question of a possible phacomatosis, namely a Klippel-Trenauney type syndrome. Alternatively, given the association of angiomatoses with a high-arched palate, hypothyroidism, lipoma, pectus in the children, and the skin lesion, the Bannayan-Riley-Ruvalcaba syndrome could also be considered. To the best of our knowledge, this is the first time that osteomalacia has been noted in a benign vascular lesion of bone. We feel that this finding is of interest in view of the fact that most of the tumors associated with oncogenic osteomalacia are either of vascular nature or richly vascularized. It is possible that such tumors secrete a factor(s), perhaps FGF-23 or MEPE, capable of affecting renal phosphate handling. In light of this, we feel it was interesting to note that a bone vascular tumor may be associated with a type of localized osteomalacia. Current studies are also focused on the ability of skeletal stem cells to repair various hard tissues by either direct orthotopic transplantation or by systemic injection. To date, our studies have shown the effectiveness of stem cell regenerative therapy in experimental animal models. We have optimized the culture conditions for the expansion of stem cells, in the laboratory, determined an appropriate carrier and locally transplanted to the site of a bony defect in dogs. Successful regeneration of bony defects that would not otherwise heal by cells in the local microenvironment has been shown in both calvarial defects. Because of these successful findings in animal models, we are hoping to embark on clinical trials to regenerate bone in humans by submitting an IND to the FDA in the near future.